Osteoarthritis (OA) is a progressive degenerative joint disease characterized by the degeneration of articular cartilage and the growth and reconstitution of subchondral bone. The symptoms are stiffness, restriction of the movement, pain, and the like and the incidence is higher with increasing age. Due to little repair capacity of cartilage, there is no radical cure for osteoarthritis and current therapy is aimed to control pain by limiting exercise and using an analgesic. If the symptoms have progressed and the disease has reached the end stage, artificial joint replacement is performed to excise degenerative articular cartilage and cover the site with a metal cover.
In an attempt to develop a cartilage repair promoter, compounds or proteins for promoting the growth of chondrocytes have been searched for, but only bone morphogenetic proteins (BMPs) have been discovered as proteins that actually increase cartilage tissue. However, BMPs have the effect of, after increasing cartilage, hypertrophying the chondrocytes and replacing them with bone, which causes problems in use for the treatment of articular cartilage. In recent years, it has been pointed out that the acceleration of chondrocyte hypertrophy is involved in the degeneration of articular cartilage and consequently the prevention of chondrocyte hypertrophy has become one of the main targets in the treatment of osteoarthritis. Target molecules that have been identified until now include Hedgehog (Non Patent Literature 1) and Hif-2α (Non Patent Literature 2 and 3). It has been also reported that transient activation of β-catenin signaling induces thickening of articular cartilage (Non Patent Literature 4).
Regenerative medicine for the treatment of cartilage injury such as articular cartilage injury and growth plate injury caused by trauma, disturbance of blood circulation, or the like has also been studied using stem cell transplantation. However, cartilage-like cells induced from stem cells tend to hypertrophy, which poses problems (Non Patent Literature 5).
Chondrodysplasia, which is included in skeletal dysplasia, is a general term for various kinds of diseases that cause dwarfism, skeletal growth disorder, skeletal deformation, and the like due to congenital disorder of the cartilage primordium and the growth plate. Chondrodysplasia is often caused by mutations of various kinds of genes involved in chondrocyte differentiation (Non Patent Literature 6). The clinical conditions are related to the disorder of chondrocyte differentiation, which includes both cases where chondrocyte differentiation is enhanced and where chondrocyte differentiation is inhibited. Hypertrophy of chondrocytes is one aspect of chondrocyte differentiation. There has been desired the development of a drug capable of controlling chondrocyte differentiation as a therapeutic agent for chondrodysplasia. Another possibility is a therapy in which chondrocytes are implanted so as to normalize the growth of some of the growth plates in chondrodysplasia patients.